The studies that make up this project have several related objectives that include: 1) an understanding of the specific acute and chronic cognitive effects of alcohol; 2) the use of drug probes and models to provide a complementary view of the determinants of learning and remembering using brain imaging techniques; 3) the development of pharmacological models of impaired cognition as expressed in different neuropsychiatric disorders; 4) uncovering cognitive deficits in alcoholics that ordinarily might not be readily apparent but would be expressed under drug challenge conditions. To meet these objectives normal volunteers, alcoholics and other neuropsychiatric disorder patients were studied in repeat measure crossover designs using several contrasting classes of drugs including benzodiazepines, serotoninergic drugs, drugs that affect the cholinergic nervous system and drugs that interact with the NMDA receptor. Previously validated cognitive neuroscience methods were used to assess and contrast the cognitive effects of these agents in different populations of patients. Detoxified alcoholics, treated with benzodiazepines (which mimics many of the effects of alcohol in the alcoholic), demonstrate a dramatic impairment in reflective cognitive functioning and inhibitory functions. This form of impairment is not nearly as apparent under placebo test conditions; furthermore, this deficit is not secondary to changes in many other cognitive domains, such as those involved in learning and remembering. In addition, access to what is in knowledge memory is qualitatively different under benzodiazepine test conditions (compared to placebo) and this is not the case in normal volunteers. Similarly, polydrug abusing patients demonstrate a pattern of cognitive changes in response to both benzodiazepine and stimulant (amphetamine) drug challenges. These findings provide some new perspective, in cognitive terms, of ways that alcohol and other psychoactive drugs alter mental functions in alcoholics and polydrug abusers that are distinguishable from the effects of alcohol in normals. Parallel studies have explored the role of awareness in memory using benzodiazepines as a tool for altering cognitive functioning. Other studies have been designed to examine whether the effects of alcohol on attention are selective and parallel the changes seen in other cognitive domains (such as those involved in learning and remembering). This research has the dual goal of utilizing drug probes for exploring the differentiated nature of attention (as well as learning and memory) while at the same time providing new, and clinically relevant, information about the cognitive effects of alcohol. These attentional-cognitive studies were designed to contrast the effects of alcohol on goal-directed (or top down) control processes with stimulus-driven (or bottom-up) cognitive functions. Goal-directed attention requires the inhibition of the stimulus-driven information. Because previous studies have demonstrated (suggested) that one consequence of alcohol use is a reduction in the ability to inhibit processing of irrelevant stimuli (i.e., restrict the spatial focus of attention), we hypothesize that acute alcohol use will impair the goal-directed control of attention, while leaving the stimulus driven control relatively intact. Findings appear to confirm this hypothesis. Chronic alcohol abuse, as seen in detoxified alcoholics, has been associated with a similar impairment in the ability to inhibit processing of irrelevant stimuli. We have also demonstrated, in both young and elderly normal volunteers, that the effects of other psychoactive agents, such as drugs that effect the NMDA receptor, mimic the cognitive changes expressed in normal aging but not that of amnesia or dementia. Ketamine also potentiates the cognitive response to both benzodiazepines and cholinergic antagonists (such as scopolamine). In general the cognitive effects of each of these classes of drugs are largely independent of their sedative effects. In a study of early and middle stage Alzheimer's disease patients, we were unable to demonstrate positive cognitive effects of stimulant treatments despite successful behavioral activation in these patients. This confirms previous findings from our laboratory demonstrating a dissociation between mood and stimulant effects of several drugs and their cognitive effects (including effects on learning, memory, attention and perception).